Multiple sclerosis is a demyelinating disease affecting the central nervous system, primarily of yong adults. It is a common disease which affects one in 2000 persons. Epidemiological studies have indicated that there is a high risk of MS0among family members of MS patients, but strict genetic inheritance has not been proven. Recent work has shown some correlation between susceptibility to MS and histocompability type. An experimental disease termed experimental allergic encephalomyelitis, EAE, has long been studied as a possible model for the human disease, MS. Using inbred populationsof rats, we have recently shown that susceptibility to EAE depends in part on the presence of an autosomal dominant immune response gene, Ir-EAE, which is linked to the major histocompatibility locus of this species. When the genes of EAE susceptible and resistant rat strains are mixed by appropriate cross breeding, susceptibility t to EAE still depends on the presence of the Ir-EAE gene. But now there are other factors which modify the disease process so that the may be very mild, or absent, even in a genetically susceptible individual. This sort of incomplete expressions of a disease process which is controlled by a histocompatibility linked gene and modified by other genes, is exactly what would be predicted for human diseases which may be controlled by histocompatibility linked immune response genes. The purpose of this project is to determine in family studies whether MS susceptibility and major histocompatibility antigens are inherited together, and to identify the factors in the human and experimental disease which determine susceptibility and the severity of clinical course. Data obtained from these studies may lead to a rational form of immunotherapy for multiple selerosis.